The mammalian citrate transporter mINDY (I'm not dead yet) and its protective role in hepatic metabolism [thesis]

Martin André Daniels, Universitätsbibliothek Der FU Berlin
2021
The soaring global prevalence of metabolic disease including obesity, type 2 diabetes mellitus and NAFLD warrants the search for novel pharmacological targets. Across species, decreased function of the transmembrane carboxylate transporter mINDY (I'm not dead yet) confers a metabolic phenotype akin to caloric restriction, including protection against diet-induced obesity, insulin resistance, and hepatic steatosis. However, the underlying mechanism is not fully understood. Based on mINDY's high
more » ... xpression levels in mammalian livers, we examined to what extent liver-specific deletion of mINDY contributes to the protective phenotype observed in the whole-body mINDY knockout (INKO) model. We were the first to establish a liver-specific conditional mINDY knockout (LINKO) mouse. We performed comprehensive metabolic phenotyping, including body composition, glucose disposal, gas exchange and insulin sensitivity over 16 weeks across three dietary regimens of differing caloric density: Normal chow diet (NCD), high-fat diet (HFD) and high-fat diet with sucrose-enriched water (HFD+S). We assessed capacity for glucose production in LINKO primary hepatocytes and screened for gene expression changes in LINKO liver samples. When compared to WT controls, LINKO mice did not show differences in body weight and length, body composition and response to intraperitoneal glucose tolerance tests. In hyperinsulinemic-euglycemic clamps, glucose infusion rates did not differ between the groups; however, we observed suppressed glycolysis and increases in clamp glucose clearance and glycogen synthesis in HFD-fed LINKO mice, relative to WT controls. Respirometry yielded conflicting results, with LINKO mice in the HFD cohort showing slightly increased energy expenditure relative to WT controls, but the opposite effect occurring in the HFD+S-cohort. Respiratory exchange ratio was significantly elevated in HFD-fed LINKO homozygotes compared to WT controls, indicating a shift towards carbohydrate catabolism. LINKO primary hepatocytes showed increa [...]
doi:10.17169/refubium-28957 fatcat:lrezyxikwjdltegjax26sgq7wq